Two human kidneys harbor nearly 1.8 million glomerular capillary tufts. Each glomerular tuft resides within Bowman's space. The capsule circumscribing this space is lined by parietal epithelial cells that transition into tubular epithelia forming the proximal nephron. The glomerular capillary tuft derives from an afferent arteriole that forms a branching capillary bed embedded in mesangial matrix (Fig. 277-1). This capillary network funnels into an efferent arteriole, which passes filtered blood into cortical peritubular capillaries or medullary vasa recta that supply and exchange with a folded tubular architecture. Hence the glomerular capillary tuft, fed and drained by arterioles, represents an arteriolar portal system. Fenestrated endothelial cells resting on a glomerular basement membrane (GBM) line glomerular capillaries. Delicate foot processes extending from epithelial podocytes shroud the outer surface of these capillaries, and podocytes interconnect to each other by slit-pore membranes forming a selective filtration barrier.
Glomerular architecture. A. The glomerular capillaries form from a branching network of renal arteries, arterioles, leading to an afferent arteriole, glomerular capillary bed (tuft), and a draining efferent arteriole (modified from Hypertension 5:8–16, 1983). B. Scanning electron micrograph of podocytes that line the outer surface of the glomerular capillaries (arrow shows foot process). C. Scanning electron micrograph of the fenestrated endothelia lining the glomerular capillary. D. The various normal regions of the glomerulus on light microscopy (A–C, courtesy of Dr. Vincent Gattone, Indiana University; with permission).
The glomerular capillaries filter 120–180 L/d of plasma water containing various solutes for reclamation or discharge by downstream tubules. Most large proteins and all cells are excluded from filtration by a physicochemical barrier governed by pore size and negative electrostatic charge. The mechanics of filtration and reclamation are quite complicated for many solutes (Chap. 271). For example, in the case of serum albumin, the glomerulus is an imperfect barrier. Although albumin has a negative charge, which would tend to repel the negatively charged GBM, it only has a physical radius of 3.6 nm, while pores in the GBM and slit-pore membranes have a radius of 4 nm. Consequently, considerable amounts of albumin (estimates range from 4000 to 9000 mg/d) inevitably cross the filtration barrier to be reclaimed by megalin and cubilin receptors along the proximal tubule. Remarkably, humans with normal nephrons do not excrete more than 8–10 mg of albumin in daily voided urine. This amount of albumin, and other proteins, can rise to gram quantities following glomerular injury.
The breadth of diseases affecting the glomerulus is expansive because the glomerular capillaries can be injured in a variety of ways, producing many different lesions and several unique changes to the urinalysis. Some order to this vast subject is brought by grouping all of these diseases into a smaller number of clinical syndromes.
Pathogenesis of Glomerular Disease
There are many forms of glomerular disease with pathogenesis variably linked to the presence of genetic mutations, infection, toxin exposure, autoimmunity, atherosclerosis, hypertension, emboli, thrombosis, or diabetes mellitus. Even after careful study, however, the cause often remains unknown, and the lesion is called idiopathic. Specific or unique features of pathogenesis are mentioned with the description of each of the glomerular diseases later in this chapter.
Some glomerular diseases result from genetic mutations producing familial disease. (1) Congenital nephrotic syndrome from mutations in NPHS1 (nephrin) and NPHS2 (podocin) affect the slit-pore membrane at birth, and TRPC6 cation channel mutations in adulthood produce focal segmental glomerulosclerosis (FSGS). (2) Partial lipodystrophy from mutations in genes encoding lamin A/C or PPAR cause a metabolic syndrome that can be associated with membranoproliferative glomerulonephritis (MPGN), which is sometimes accompanied by dense deposits and C3 nephritic factor. (3) Alport's syndrome, from mutations in the genes encoding for the 3, 4, or 5 chains of type IV collagen, produces split-basement membranes with glomerulosclerosis. (4) Lysosomal storage diseases, such as -galactosidase A deficiency causing Fabry's disease and N-acetylneuraminic acid hydrolase deficiency causing nephrosialidosis, produce FSGS.
Systemic hypertension and atherosclerosis can produce pressure stress, ischemia, or lipid oxidants that lead to chronic glomerulosclerosis.Malignant hypertension can quickly complicate glomerulosclerosis with fibrinoid necrosis of arterioles and glomeruli, thrombotic microangiopathy, and acute renal failure. Diabetic nephropathy is an acquired sclerotic injury associated with thickening of the GBM secondary to the long-standing effects of hyperglycemia, advanced glycosylation end-products, and reactive oxygen species.
Inflammation of the glomerular capillaries is called glomerulonephritis. Most glomerular or mesangial antigens involved in immune-mediated glomerulonephritis are unknown (Fig. 277-2). Glomerular epithelial or mesangial cells may shed them or express epitopes that mimic other immunogenic proteins made elsewhere in the body. Bacteria, fungi, and viruses can directly infect the kidney producing their own antigens. Autoimmune diseases like idiopathic membranous glomerulonephritis (MGN) or MPGN are confined to the kidney, while systemic inflammatory diseases like lupus nephritis or Wegener's granulomatosis spread to the kidney, causing secondary glomerular injury. Antiglomerular basement membrane disease producing Goodpasture's syndrome primarily injures both the lung and kidney because of the narrow distribution of the 3 NC1 domain of type IV collagen that is the target antigen.
The glomerulus is injured by a variety of mechanisms. A. Preformed immune deposits can precipitate from the circulation and collect along the glomerular basement membrane (GBM) in the subendothelial space or can form in situ along the subepithelial space. B. Immunofluorescent staining of glomeruli with labeled anti-IgG demonstrating linear staining from a patient with anti-GBM disease or immune deposits from a patient with membranous glomerulonephritis. C. The mechanisms of glomerular injury have a complicated pathogenesis. Immune deposits and complement deposition classically draw macrophages and neutrophils into the glomerulus. T lymphocytes may follow to participate in the injury pattern as well. D. Amplification mediators as locally derived oxidants and proteases expand this inflammation, and, depending on the location of the target antigen and the genetic polymorphisms of the host, basement membranes are damaged with either endocapillary or extracapillary proliferation.
While the adaptive immune response is similar to that of other tissues, early T cell activation plays an important role in the mechanism of glomerulonephritis. Antigens presented by class II major histocompatibility complex (MHC) molecules on macrophages and dendritic cells in conjunction with associative recognition molecules engage the CD4/8 T cell repertoire. Local activation of Toll-like receptors on glomerular cells, deposition of immune complexes, or complement injury to glomerular structures induces mononuclear cell infiltration, which subsequently leads to an adaptive immune response attracted to the kidney by local release of chemokines. Neutrophils, macrophages, and T cells are drawn by chemokines into the glomerular tuft, where they react with antigens and epitopes on or near somatic cells or their structures, producing more cytokines and proteases that damage the mesangium, capillaries, and/or the GBM.
Mononuclear cells by themselves can injure the kidney, but autoimmune events that damage glomeruli classically produce a humoral immune response. Poststreptococcal glomerulonephritis, lupus nephritis, and idiopathic membranous nephritis typically are associated with immune deposits along the GBM, while anti-GBM antibodies are produced in anti-GBM disease. Preformed circulating immune complexes can precipitate along the subendothelial side of the GBM, while other immune deposits form in situ on the subepithelial side. These latter deposits accumulate when circulating autoantibodies find their antigen trapped along the subepithelial edge of the GBM. Immune deposits in the glomerular mesangium may result from the deposition of preformed circulating complexes or in situ antigen-antibody interactions. Immune deposits can stimulate the release of local proteases and activate the complement cascade, producing C5-9 attack complexes. In addition, local oxidants can damage glomerular structures, producing proteinuria and effacement of the podocytes. Overlapping etiologies or pathophysiologic mechanisms can produce similar glomerular lesions, suggesting that downstream molecular and cellular responses often converge towards common patterns of injury.
Progression of Glomerular Disease
Persistent glomerulonephritis that worsens renal function is always accompanied by interstitial nephritis, renal fibrosis, and tubular atrophy . What is not so obvious, however, is that renal failure in glomerulonephritis best correlates histologically with the appearance of tubulointerstitial nephritis rather than with the type of inciting glomerular injury.
Loss of renal function due to interstitial damage can be explained hypothetically by several mechanisms. The simplest explanation is that urine flow is impeded by tubular obstruction as a result of interstitial inflammation and fibrosis. Thus, obstruction of the tubules with debris or by extrinsic compression results in aglomerular nephrons. A second mechanism suggests that interstitial changes, including interstitial edema or fibrosis, alter tubular and vascular architecture and thereby compromise the normal tubular transport of solutes and water from tubular lumen to vascular space. This failure increases the solute and water content of the tubule fluid, resulting in isothenuria and polyuria. Adaptive mechanisms related to tubuloglomerular feedback also fail, resulting in a reduction of renin output from the juxtaglomerular apparatus of glomeruli trapped by interstitial inflammation. Consequently, the local vasoconstrictive influence of angiotensin II on the glomerular arterioles decreases, and filtration drops owing to a generalized decrease in arteriolar tone. A third mechanism involves changes in vascular resistance due to damage of peritubular capillaries. The cross-sectional volume of these capillaries is decreased in areas of interstitial inflammation, edema, or fibrosis. These structural alterations in vascular resistance affect renal function through two mechanisms. First, tubular cells are very metabolically active, and, as a result, decreased perfusion could lead to ischemic injury. Second, impairment of glomerular arteriolar outflow leads to increased intraglomerular hypertension in less involved glomeruli; this selective intraglomerular hypertension aggravates and extends mesangial sclerosis and glomerulosclerosis to less-involved glomeruli. Regardless of the exact mechanism, early acute tubulointerstitial nephritis suggests potentially recoverable renal function, while the development of chronic interstitial fibrosis prognosticates a permanent loss.
Persistent damage to glomerular capillaries spreads to the tubulointerstitium in association with proteinuria. There is an untested hypothesis that efferent arterioles leading from inflamed glomeruli carry forward inflammatory mediators, which induces downstream interstitial nephritis, resulting in fibrosis. Glomerular filtrate from injured glomerular capillaries adherent to Bowman's capsule may also be misdirected to the periglomerular interstitium. Most nephrologists believe, however, that proteinuric glomerular filtrate forming tubular fluid is the primary route to downstream tubulointerstitial injury, although none of these hypotheses are mutually exclusive.
The simplest explanation for the effect of proteinuria on the development of interstitial nephritis is that increasingly severe proteinuria, carrying activated cytokines and lipoproteins producing reactive oxygen species, triggers a downstream inflammatory cascade in and around epithelial cells lining the tubular nephron. These effects induce T lymphocyte and macrophage infiltrates in the interstitial spaces along with fibrosis and tubular atrophy. The details of this process are described in Chap. 272.
Tubules disappear following direct damage to their basement membranes, leading to decondensation and epithelial-mesenchymal transitions forming more interstitial fibroblasts at the site of injury. Transforming growth factor (TGF-), fibroblast growth factor 2, and platelet-derived growth factor (PDGF) are particularly active in this transition. With persistent nephritis, fibroblasts multiply and lay down tenascin and a fibronectin scaffold for the polymerization of new interstitial collagens I/III. These events form scar tissue through a process called fibrogenesis. In experimental studies, bone morphogenetic protein 7 and hematopoietic growth factor can reverse early fibrogenesis and preserve tubular architecture. When fibroblasts outdistance their survival factors, they apoptose, and the permanent renal scar becomes acellular, leading to irreversible renal failure.
Approach to the Patient: Glomerular Disease
Hematuria, Proteinuria, and Pyuria
Patients with glomerular disease usually have some hematuria with varying degrees of proteinuria. Hematuria is typically asymptomatic. As little as 3–5 red blood cells in the spun sediment from first voided morning urine is suspicious. The diagnosis of glomerular injury can be delayed because patients will not realize they have microscopic hematuria, and only rarely with the exception of IgA nephropathy and sickle cell disease is gross hematuria present. When working up microscopic hematuria, perhaps accompanied by minimal proteinuria (less than 500 mg/24 h), it is important to exclude anatomic lesions, such as malignancy of the urinary tract, particularly in older men. Microscopic hematuria may also appear with the onset of benign prostatic hypertrophy, interstitial nephritis, papillary necrosis, renal stones, cystic kidney diseases, or renal vascular injury. However, when red blood cell casts or dysmorphic red blood cells are found in the sediment, glomerulonephritis is likely.
Sustained proteinuria less than 1–2 g/24 h is also commonly associated with glomerular disease. Patients often will not know they have proteinuria unless they become edematous or notice foamy urine on voiding. Sustained proteinuria has to be distinguished from lesser amounts of so-called benign proteinuria in the normal population (Table 277-1). This latter class of proteinuria is nonsustained, generally less than 1 g/24 h, and is sometimes called functional or transient proteinuria. Fever, exercise, obesity, sleep apnea, emotional stress, and congestive heart failure can explain transient proteinuria. Proteinuria only seen with upright posture is called orthostatic proteinuria. Occasionally, isolated proteinuria sustained over multiple clinic visits is found in diabetic nephropathy, nil lesion, mesangioproliferative glomerulonephritis, and FSGS. Proteinuria in most adults with glomerular disease is nonselective, containing albumin and a mixture of other serum proteins, while in children with nil lesion from minimal change disease, the proteinuria is selective and largely composed of albumin.
aAlbumin detected by radioimmunoassay.
Some patients with inflammatory glomerular disease, such as acute poststreptococcal glomerulonephritis or MPGN, may have pyuria caused by the presence of considerable numbers of leukocytes in the urine. This latter finding has to be distinguished from urine infected with bacteria.
Various forms of glomerular injury can also be parsed into several distinct syndromes on clinical grounds (Table 277-2). These syndromes, however, are not always mutually exclusive. There is an acute nephritic syndrome producing 1–2 g/24 h of proteinuria, hematuria with red blood cell casts, pyuria, hypertension, fluid retention, and a rise in serum creatinine associated with a reduction in glomerular filtration. If glomerular inflammation develops slowly, the serum creatinine will rise gradually over many weeks, but if the serum creatinine rises quickly, particularly over a few days, acute nephritis is sometimes called rapidly progressive glomerulonephritis (RPGN); the histopathologic term crescentic glomerulonephritis refers to the clinical occurrence of RPGN in a patient with this characteristic glomerular lesion. When patients with RPGN present with lung hemorrhage from Goodpasture's syndrome, antineutrophil cytoplasmic antibodies (ANCA) small-vessel vasculitis, lupus erythematosus, or cryoglobulinemia, they are often diagnosed as having a pulmonary-renal syndrome. Nephrotic syndrome describes the onset of heavy proteinuria (>3.0 g/24 h), hypertension, hypercholesterolemia, hypoalbuminemia, edema/anasarca, and microscopic hematuria; if only large amounts of proteinuria are present without clinical manifestations, the condition is sometimes called nephrotic-range proteinuria. The glomerular filtration rate (GFR) in these patients may initially be normal or, rarely, higher than normal, but with persistent hyperfiltration and continued nephron loss, it typically declines over months to years. Patients with a basement membrane syndrome either have genetically abnormal basement membranes or an autoimmune response to basement membrane collagen IV associated with microscopic hematuria, mild to heavy proteinuria, and hypertension with variable elevations in serum creatinine. Glomerular-vascular syndrome describes patients with vascular injury producing hematuria and moderate proteinuria. Affected individuals can have vasculitis, thrombotic microangiopathy, antiphospholipid syndrome, or, more commonly, a systemic disease such as atherosclerosis, cholesterol emboli, hypertension, sickle cell anemia, and autoimmunity. Infectious diseases-associated syndrome is most important if one has an international perspective. Save for subacute bacterial endocarditis in the Western Hemisphere, malaria and schistosomiasis may be the most common causes of glomerulonephritis throughout the world, closely followed by HIV and chronic hepatitis B and C. These infectious diseases produce a variety of inflammatory reactions in glomerular capillaries, ranging from nephrotic syndrome to acute nephritic injury, and yield urinalyses that demonstrate a combination of hematuria and proteinuria.
These six general categories of syndromes are usually determined at the bedside with the help of a history and physical examination, blood chemistries, renal ultrasound, and urinalysis. These initial studies help frame further diagnostic work up that typically involves some testing of the serum for the presence of various proteins (HIV and hepatitis B and C antigens), antibodies [anti-GBM, antiphospholipid, ASO, anti-DNAase, antihyaluronidase, ANCA, anti-DNA, cryoglobulins, anti-HIV, and anti-hepatitis B and C antibodies] or depletion of complement components (C3 and C4). The bedside history and physical examination can also help determine whether the glomerulonephritis is isolated to the kidney (primary glomerulonephritis) or is part of a systemic disease (secondary glomerulonephritis). When confronted with an abnormal urinalysis and elevated serum creatinine, with or without edema or congestive heart failure, one must consider whether the glomerulonephritis is acute or chronic. This assessment is best made by careful history (last known urinalysis or serum creatinine during pregnancy or insurance physical, evidence of infection, or use of medication or recreational drugs); the size of the kidneys on renal ultrasound examination; and how the patient feels at presentation. Chronic glomerular disease often presents with decreased kidney size. Patients who quickly develop renal failure are fatigued and weak; feel miserable; often have uremic symptoms associated with nausea, vomiting, fluid retention, and somnolence. Primary glomerulonephritis presenting with renal failure that has progressed slowly, however, can be remarkably asymptomatic, as are patients with acute glomerulonephritis without much loss in renal function. Once this initial information is collected, selected patients who are clinically stable, have adequate blood clotting parameters, and are willing to receive treatment are encouraged to have a renal biopsy. Biopsies can be done safely with an ultrasound-guided biopsy gun.
A renal biopsy in the setting of glomerulonephritis can quickly identify the type of glomerular injury and often suggests a course of treatment. The biopsy is processed for light microscopy using stains for hematoxylin and eosin (H and E) to assess cellularity and architecture, periodic acid-Schiff (PAS) to stain carbohydrate moieties in the membranes of the glomerular tuft and tubules, Jones-methenamine silver to enhance basement membrane structure, Congo red for amyloid deposits, and Masson's trichrome to identify collagen deposition and assess the degree of glomerulosclerosis and interstitial fibrosis. Biopsies are also processed for direct immunofluorescence using conjugated antibodies against IgG, IgM, and IgA to detect the presence of "lumpy-bumpy" immune deposits or "linear" IgG or IgA antibodies bound to GBM, antibodies against trapped complement proteins (C3 and C4), or specific antibodies against a relevant antigen. High-resolution electron microscopy can clarify the principal location of immune deposits and the status of the basement membrane.
Each region of a renal biopsy is assessed separately. By light microscopy, glomeruli (at least 10 and ideally 20) are reviewed individually for discrete lesions; less than 50% involvement is considered focal, and more than 50% is diffuse. Injury in each glomerular tuft can be segmental, involving a portion of the tuft, or global, involving most of the glomerulus. Glomeruli can have proliferative characteristics, showing increased cellularity. When cells in the capillary tuft proliferate, it is called endocapillary, and when cellular proliferation extends into Bowman's space, it is called extracapillary. Synechiae are formed when epithelial podocytes attach to Bowman's capsule in the setting of glomerular injury; crescents, which in some cases may be the extension of synechiae, develop when fibrocellular/fibrin collections fill all or part of Bowman's space; and sclerotic glomeruli show acellular, amorphous accumulations of proteinaceous material throughout the tuft with loss of functional capillaries and normal mesangium. Since age-related glomerulosclerosis is common in adults, one can estimate the background percentage of sclerosis by dividing the patient's age in half and subtracting 10. Immunofluorescent and electron microscopy can detect the presence and location of subepithelial,subendothelial, or mesangial immune deposits, or reduplication or splitting of the basement membrane. In the other regions of the biopsy, the vasculature surrounding glomeruli and tubules can show angiopathy, vasculitis, the presence of fibrils, or thrombi. The tubules can be assessed for adjacency to one another; separation can be the result of edema, tubular dropout, or collagen deposition resulting from interstitial fibrosis. Interstitial fibrosis is an ominous sign of irreversibility and progression to renal failure.
Acute Nephritic Syndromes
Acute nephritic syndromes classically present with hypertension, hematuria, red blood cell casts, pyuria, and mild to moderate proteinuria. Extensive inflammatory damage to glomeruli can cause a fall in GFR and eventually produce uremic symptoms with salt and water retention, leading to edema and hypertension.
Poststreptococcal glomerulonephritis is prototypical for acute endocapillary proliferative glomerulonephritis. The incidence of poststreptococcal glomerulonephritis is decreasing in Western countries, and it is typically sporadic. Epidemic cases are still seen, though less commonly. Acute poststreptococcal glomerulonephritis typically affects children between the ages of 2 and 14 years, but 10% of cases are patients older than 40. It is more common in males, and the familial or cohabitant incidence is as high as 40%. Skin and throat infections with particular M types of streptococci (nephritogenic strains) antedate glomerular disease; M types 47, 49, 55, 2, 60, and 57 are seen following impetigo and M types 1, 2, 4, 3, 25, 49, and 12 with pharyngitis. Poststreptococcal glomerulonephritis due to impetigo develops 2–6 weeks after skin infection and 1–3 weeks after streptococcal pharyngitis.
The renal biopsy in poststreptococcal glomerulonephritis demonstrates hypercellularity of mesangial and endothelial cells, glomerular infiltrates of polymorphonuclear leukocytes, granular subendothelial immune deposits of IgG, IgM, C3, C4, and C5-9, and subepithelial deposits (which appear as "humps") Poststreptococcal glomerulonephritis is an immune-mediated disease involving putative streptococcal antigens, circulating immune complexes, and activation of complement in association with cell-mediated injury. Many candidate antigens have been proposed over the years; three such candidates from nephritogenic streptococci are zymogen, a precursor of exotoxin B; glyceraldehyde phosphate dehydrogenase, also known as presorbing antigen (PA-Ag); and streptokinase. All have a biochemical affinity for GBMs, and in this location they may act as a target for antibodies.
The classic presentation is an acute nephritic picture with hematuria, pyuria, red blood cell casts, edema, hypertension, and oliguric renal failure, which may be severe enough to appear as RPGN. Systemic symptoms of headache, malaise, anorexia, and flank pain (due to swelling of the renal capsule) are reported in as many as 50% of cases. Five percent of children and 20% of adults have proteinuria in the nephrotic range. In the first week of symptoms, 90% of patients will have a depressed CH50 and decreased levels of C3 with normal levels of C4. Positive rheumatoid factor (30–40%), cryoglobulins and circulating immune complexes (60–70%), and ANCA against myeloperoxidase (10%) are also reported. Positive cultures for streptococcal infection are inconsistently present (10–70%), but increased titers of ASO (30%), anti-DNAase (70%) or antihyaluronidase antibodies (40%) can help confirm the diagnosis. Consequently, the diagnosis of poststreptococcal glomerulonephritis rarely requires a renal biopsy. A subclinical disease is reported in some series to be four to five times as common as clinical nephritis, and these latter cases are characterized by asymptomatic microscopic hematuria with low serum complement levels. Treatment is supportive, with control of hypertension, edema, and dialysis as needed. Antibiotic treatment for streptococcal infection should be given to all patients and their cohabitants. There is no role for immunosuppressive therapy, even in the setting of crescents. Recurrent poststreptococcal glomerulonephritis is rare despite repeated streptococcal infections. Early death is rare in children but does occur in the elderly. Overall, the prognosis is good, with permanent renal failure being very uncommon (1–3%), and even less so in children. Complete resolution of the hematuria and proteinuria in children occurs within 3–6 weeks of the onset of nephritis.
Subacute Bacterial Endocarditis
Endocarditis-associated glomerulonephritis is typically a complication of subacute bacterial endocarditis, particularly in patients who remain untreated for a long time, have negative blood cultures, or have right-sided endocarditis. Glomerulonephritis is unusual in acute bacterial endocarditis because it takes 10–14 days to develop immune complex–mediated injury, by which time the patient has been treated, often with emergent surgery. Grossly, the kidneys in subacute bacterial endocarditis have subcapsular hemorrhages with a "flea-bitten" appearance, and microscopy on renal biopsy reveals a focal proliferation around foci of necrosis associated with abundant mesangial, subendothelial, and subepithelial immune deposits of IgG, IgM, and C3. Patients who present with a clinical picture of RPGN have crescents. Embolic infarcts or septic abscesses may also be present. The pathogenesis hinges on the renal deposition of circulating immune complexes in the kidney with complement activation. Patients present with gross or microscopic hematuria, pyuria, and mild proteinuria or, less commonly, RPGN with rapid loss of renal function. A normocytic anemia, elevated erythrocyte sedimentation rate, hypocomplementemia, high titers of rheumatoid factor, type III cryoglobulins, and circulating immune complexes are often present. Levels of serum creatinine may be elevated at diagnosis, but with modern therapy there is little progression to chronic renal failure. Primary treatment is eradication of the infection with 4–6 weeks of antibiotics, and if accomplished expeditiously, the prognosis for renal recovery is good.
As variants of persistent bacterial infection in blood, glomerulonephritis can occur in patients with ventriculoatrial and ventriculoperitoneal shunts; pulmonary, intra-abdominal, pelvic, or cutaneous infections; and infected vascular prostheses. The clinical presentation of these conditions is variable and includes proteinuria, microscopic hematuria, and acute renal failure. Blood cultures are usually positive and serum complement levels low, and there may be elevated levels of C-reactive proteins, rheumatoid factor, antinuclear antibodies, and cryoglobulins. Renal lesions include membranoproliferative glomerulonephritis (MPGN), diffuse proliferative glomerulonephritis (DPGN), or mesangioproliferative glomerulonephritis, sometimes leading to RPGN. Treatment focuses on eradicating the infection, with most patients treated as if they have endocarditis.
Lupus nephritis is a common and serious complication of systemic lupus erythematosus (SLE) and most severe in African-American female adolescents. Thirty to fifty percent of patients will have clinical manifestations of renal disease at the time of diagnosis, and 60% of adults and 80% of children develop renal abnormalities at some point in the course of their disease. Lupus nephritis results from the deposition of circulating immune complexes, which activate the complement cascade leading to complement-mediated damage, leukocyte infiltration, activation of procoagulant factors, and release of various cytokines. In situ immune complex formation following glomerular binding of nuclear antigens may also play a role in renal injury. The presence of antiphospholipid antibodies may trigger a thrombotic microangiopathy in a minority of patients.
The clinical manifestations, course of disease, and treatment of lupus nephritis are closely linked to the renal pathology. The most common clinical sign of renal disease is proteinuria, but hematuria, hypertension, varying degrees of renal failure, and an active urine sediment with red blood cell casts can all be present. Although significant renal pathology can be found on biopsy even in the absence of major abnormalities in the urinalysis, most nephrologists do not biopsy patients until the urinalysis is convincingly abnormal. The extrarenal manifestations of lupus are important in establishing a firm diagnosis of systemic lupus because, while serologic abnormalities are common in lupus nephritis, they are not diagnostic. Anti-dsDNA antibodies that fix complement correlate best with the presence of renal disease. Hypocomplementemia is common in patients with acute lupus nephritis (70–90%) and declining complement levels may herald a flare. Renal biopsy, however, is the only reliable method of identifying the morphologic variants of lupus nephritis.
The World Health Organization (WHO) workshop in 1974 first outlined several distinct patterns of lupus-related glomerular injury; these were modified in 1982. In 2004 the International Society of Nephrology in conjunction with the Renal Pathology Society again updated the classification. This latest version of lesions seen on biopsy (Table 277-3) best defines clinicopathologic correlations, provides valuable prognostic information, and forms the basis for modern treatment recommendations. Class I nephritis describes normal glomerular histology by any technique or normal light microscopy with minimal mesangial deposits on immunofluorescent or electron microscopy. Class II designates mesangial immune complexes with mesangial proliferation. Both Class I and II lesions are typically associated with minimal renal manifestation and normal renal function; nephrotic syndrome is rare. Patients with lesions limited to the renal mesangium have an excellent prognosis and generally do not need therapy for their lupus nephritis.
Note: Revised in 2004 by the International Society of Nephrology-Renal Pathology Society Study Group.
The subject of lupus nephritis is presented under acute nephritic syndromes because of the aggressive and important proliferative lesions seen in Class III–V renal disease. Class III describes focal lesions with proliferation or scarring, often involving only a segment of the glomerulus (Fig. e9-10). Class III lesions have the most varied course. Hypertension, an active urinary sediment, and proteinuria are common with nephrotic-range proteinuria in 25–33% of patients. Elevated serum creatinine is present in 25% of patients. Patients with mild proliferation involving a small percentage of glomeruli respond well to therapy with steroids alone, and fewer than 5% progress to renal failure over 5 years. Patients with more severe proliferation involving a greater percentage of glomeruli have a far worse prognosis and may have lower remission rates.
Treatment of those patients is the same as that for Class IV lesions, as some nephrologists believe that Class III lesions are simply an early presentation of Class IV disease. Class IV describes global, diffuse proliferative lesions involving the vast majority of glomeruli. Patients with Class IV lesions commonly have high anti-DNA antibody titers, low serum complement, hematuria, red blood cell casts, proteinuria, hypertension, and decreased renal function; 50% of patients have nephrotic-range proteinuria. Patients with crescents on biopsy may have a rapidly progressive decline in renal function. Without treatment, this aggressive lesion has the worst renal prognosis. However, if a remission—defined as a return to near-normal renal function and proteinuria 330 mg/dL per day—is achieved with treatment, renal outcomes are excellent. Treatment must combine high-dose steroids with either cyclophosphamide or mycophenolate mofetil. Current evidence suggests that inducing a remission with administration of steroids and either cyclophosphamide or mycophenolate mofetil for 2–6 months, followed by maintenance therapy with lower doses of steroids and mycophenolate mofetil, may best balance the likelihood of successful remission with the side effects of therapy. There is no consensus on use of high-dose intravenous methylprednisolone versus oral prednisone, monthly intravenous cyclophosphamide versus daily oral cyclophosphamide, or other immunosuppressants such as cyclosporine or azathioprine. Nephrologists tend to avoid prolonged use of cyclophosphamide in patients of childbearing age without first banking eggs or sperm.
The Class V lesion describes subepithelial immune deposits producing a membranous pattern; a subcategory of Class V lesions is associated with proliferative lesions and is sometimes called mixed membranous and proliferative disease; this category of injury is treated like Class IV glomerulonephritis. Sixty percent of patients present with nephrotic syndrome or lesser amounts of proteinuria. Patients with lupus nephritis Class V, like patients with idiopathic membranous nephropathy, are predisposed to renal-vein thrombosis and other thrombolic complications. A minority of patients with Class V will present with hypertension and renal dysfunction. There are conflicting data on the clinical course, prognosis, and appropriate therapy for patients with Class V disease, which may reflect the heterogeneity of this group of patients. Patients with severe nephrotic syndrome, elevated serum creatinine, and a progressive course will probably benefit from therapy with steroids in combination with other immunosuppressive agents. Therapy with inhibitors of the renin-angiotensin system also may attenuate the proteinuria.
Patients with any of the above lesions also can transform to another lesion; hence patients often require reevaluation, including repeat renal biopsy. Lupus patients with Class VI lesions have greater than 90% sclerotic glomeruli and end-stage renal disease with interstitial fibrosis. As a group, approximately 20% of patients with lupus nephritis will reach end-stage disease, requiring dialysis or transplantation. Systemic lupus tends to become quiescent once there is renal failure, perhaps due to the immunosuppressant effects of uremia. Renal transplantation in renal failure from lupus, usually performed after approximately 6 months of inactive disease, results in allograft survival rates comparable to patients transplanted for other reasons.
Antiglomerular Basement Membrane Disease
Patients who develop autoantibodies directed against glomerular basement antigens frequently develop a glomerulonephritis termed antiglomerular basement membrane (anti-GBM) disease. When they present with lung hemorrhage and glomerulonephritis, they have a pulmonary-renal syndrome called Goodpasture's syndrome. The target epitopes for this autoimmune disease lie in the quaternary structure of 3 NC1 domain of collagen IV. MHC-restricted T cells initiate the autoantibody response because humans are not tolerant to the epitopes created by this quaternary structure. The epitopes are normally sequestered in the collagen IV hexamer and can be exposed by infection, smoking, oxidants, or solvents. Goodpasture's syndrome appears in two age groups: in young men in their late 20s and in men and women in their 60–70s. Disease in the younger age group is usually explosive, with hemoptysis, a sudden fall in hemoglobin, fever, dyspnea, and hematuria. Hemoptysis is largely confined to smokers, and those who present with lung hemorrhage as a group do better than older populations who have prolonged, asymptomatic renal injury; presentation with oliguria is often associated with a particularly bad outcome. The performance of an urgent kidney biopsy is important in suspected cases of Goodpasture's syndrome to confirm the diagnosis and assess prognosis. Renal biopsies typically show focal or segmental necrosis that later, with aggressive destruction of the capillaries by cellular proliferation, leads to crescent formation in Bowman's space
As these lesions progress, there is concomitant interstitial nephritis with fibrosis and tubular atrophy. The presence of anti-GBM antibodies and complement is recognized on biopsy by linear immunofluorescent staining for IgG (rarely IgA). In testing serum for anti-GBM antibodies, it is particularly important that the 3 NC1 domain of collagen IV alone be used as the target. This is because nonnephritic antibodies against the 1 NC1 domain are seen in paraneoplastic syndromes and cannot be discerned from assays that use whole basement membrane fragments as the binding target. Between 10–15% of sera from patients with Goodpasture's syndrome also contain ANCA antibodies against myeloperoxidase. This subset of patients has a vasculitis-associated variant, which has a surprisingly good prognosis with treatment. Prognosis at presentation is worse if there are more than 50% crescents on renal biopsy with advanced fibrosis, if serum creatinine is more than 5–6 mg/dL, if oliguria is present, or if there is a need for acute dialysis. Although frequently attempted, most of these latter patients will not respond to plasmapheresis and steroids. Patients with advanced renal failure who present with hemoptysis should still be treated for their lung hemorrhage, as it responds to plasmapheresis and can be lifesaving. Treated patients with less severe disease typically respond to 8–10 treatments of plasmapheresis accompanied by oral prednisone and cyclophosphamide in the first 2 weeks. Kidney transplantation is possible, but because there is risk of recurrence, experience suggests that patients should wait for 6 months and until serum antibodies are undetectable.
Berger first described the glomerulonephritis termed IgA nephropathy. It is classically characterized by episodic hematuria associated with the deposition of IgA in the mesangium. IgA nephropathy is one of the most common forms of glomerulonephritis worldwide. There is a male preponderance, a peak incidence in the second and third decades of life, and rare familial clustering. There are geographic differences in the prevalence of IgA nephropathy, with 30% prevalence along the Asian and Pacific Rim and 20% in southern Europe, compared to lower prevalence in norther
Europe and North America. It was initially hypothesized that variation in detection, in part, reflected regional differences in the recognition of asymptomatic microscopic hematuria or the frequency of renal biopsies. With clinical care in nephrology becoming more uniform and regional reports coming largely from larger cities, however, this variation in prevalence more likely reflects true differences among racial and ethnic groups. Clinical and laboratory evidence suggests close similarities between Henoch-Schönlein purpura and IgA nephropathy. Henoch-Schönlein purpura is distinguished clinically from IgA nephropathy by prominent systemic symptoms, a younger age (less than 20 years old), preceding infection, and abdominal complaints. Deposits of IgA are also found in the glomerular mesangium in a variety of systemic diseases, including chronic liver disease, Crohn's disease, gastrointestinal adenocarcinoma, chronic obstructive bronchiectasis, idiopathic interstitial pneumonia, dermatitis herpetiformis, mycosis fungoides, leprosy, ankylosing spondylitis, relapsing polychondritis, and Sjögren's syndrome. IgA deposition in these entities is not usually associated with clinically significant glomerular inflammation or renal dysfunction and thus is not called IgA nephropathy.
IgA nephropathy is an immune complex-mediated glomerulonephritis defined by the presence of diffuse mesangial IgA deposits often associated with mesangial hypercellularity. IgM, IgG, C3, or immunoglobulin light chains may be codistributed with IgA. IgA deposited in the mesangium is typically polymeric and of the IgA1 subclass, the pathogenic significance of which is not clear. Abnormalities have been described in IgA production by plasma cells, particularly secretory IgA; in IgA O-glycosylation; in IgA clearance, predominately by the liver; in mesangial IgA clearance and receptors for IgA; and in growth factor and cytokine-mediated events. Despite the presence of elevated serum IgA levels in 20–50% of patients, IgA deposition in skin biopsies in 15–55% of patients, or elevated levels of secretory IgA and IgA-fibronectin complexes, a renal biopsy is necessary to make the diagnosis. Although the immunofluorescent pattern of IgA on renal biopsy defines IgA nephropathy in the proper clinical context, a variety of histologic lesions may be seen on light microscopy, including DPGN; segmental sclerosis; and, rarely, segmental necrosis with cellular crescent formation, which typically presents as RPGN.
The two most common presentations of IgA nephropathy are recurrent episodes of macroscopic hematuria during or immediately following an upper respiratory infection in children (Henoch-Schönlein purpura) or asymptomatic microscopic hematuria most often seen in adults. Between episodes, the urinalysis is normal. When the hematuria persists, one finds increasing amounts of proteinuria; nephrotic syndrome, however, is uncommon. The presence or absence of proteinuria at the time of diagnosis often determines whether patients with asymptomatic hematuria are biopsied, which reflects the bias in habits of clinical practice. Proteinuria can occur late in the course of the disease. Rarely, patients can present with acute renal failure and a rapidly progressive clinical picture. IgA nephropathy is a benign disease for the majority of patients, with progression to renal failure seen in only 25–30% over 20–25 years; in fact, 5–30% of patients go into complete remission. Risk factors for the loss of renal function include the presence of hypertension or proteinuria, the absence of episodes of macroscopic hematuria, male age, older age of onset, and more severe changes on renal biopsy.
There is no agreement on optimal treatment. Both large studies that include patients with multiple glomerular diseases or small studies of patients with IgA nephropathy support the use of angiotensin-converting enzyme (ACE) inhibitors in patients with proteinuria or declining renal function. Tonsillectomy, steroid therapy, and fish oil have all been suggested in small studies to benefit select patients with IgA nephropathy. When presenting as RPGN, patients typically receive steroids, cytotoxic agents, and plasmapheresis.
ANCA Small Vessel Vasculitis
A group of patients with small-vessel vasculitis (arterioles, capillaries, and venules; rarely small arteries) and glomerulonephritis have serum ANCA; the antibodies are of two types, anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) (Chap. 319). ANCA are produced with the help of T cells and activate leukocytes and monocytes, which together damage the walls of small vessels. Endothelial injury also attracts more leukocytes and extends the inflammation. Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome belong to this group because they are ANCA-positive and have a pauci-immune glomerulonephritis with few immune complexes in small vessels and glomerular capillaries. Patients with any of these three diseases can have any combination of the above serum antibodies, but anti-PR3 antibodies are more common in Wegener's and anti-MPO antibodies are more common in microscopic polyangiitis or Churg-Strauss. While each of these diseases have some unique clinical features, most features do not predict relapse or progression, and as a group they are generally treated in the same way. Only the presence of upper-airway involvement, persistent pulmonary injury, and anti-PR3 antibodies suggests that the course of disease will be more difficult. Induction therapy usually includes some combination of plasmapheresis, methylprednisolone, and cyclophosphamide. The benefit of plasmapheresis in this setting is uncertain. The steroids are tapered soon after acute inflammation subsides, and patients are maintained on cyclophosphamide or azathioprine for up to a year to minimize the risk of relapse.
Patients with this disease classically present with fever, purulent rhinorrhea, nasal ulcers, sinus pain, polyarthralgias/arthritis, cough, hemoptysis, shortness of breath, microscopic hematuria, and 0.5–1 g/24 h of proteinuria; occasionally there may be cutaneous purpura and mononeuritis multiplex. Presentation without renal involvement is termed limited Wegener's granulomatosis, although some of these patients will show signs of renal injury later. Chest x-ray often reveals nodules and persistent infiltrates, sometimes with cavities. Biopsy of involved tissue will show a small-vessel vasculitis and adjacent noncaseating granulomas. Renal biopsies during active disease demonstrate segmental necrotizing glomerulonephritis without immune deposits. The cause of Wegner's granulomatosis is unknown. In case-controlled studies there is greater risk associated with exposure to silica dust. The disease is also more common in patients with 1 antitrypsin deficiency, which is an inhibitor of PR3.
Clinically, these patients look somewhat similar to those with Wegener's granulomatosis, except they rarely have significant lung disease or destructive sinusitis. The distinction is made on biopsy where the vasculitis in microscopic polyangiitis is without granulomas. Some patients will also have injury limited to the capillaries and venules.
When small-vessel vasculitis is associated with peripheral eosinophilia, cutaneous purpura, mononeuritis, asthma, and allergic rhinitis, a diagnosis of Churg-Strauss syndrome is considered. Hypergammaglobulinemia, elevated levels of serum IgE, or the presence of rheumatoid factor sometimes accompanies the allergic state. Lung inflammation, including fleeting cough and pulmonary infiltrates, often precedes the systemic manifestations of disease by years; lung manifestations are rarely absent. A third of patients may have exudative pleural effusions associated with eosinophils. Small-vessel vasculitis and focal segmental necrotizing glomerulonephritis can be seen on renal biopsy, usually absent eosinophils or granulomas. The cause of Churg-Strauss syndrome is autoimmune, but the inciting factors are unknown. Interestingly, some asthma patients treated with leukotriene receptor antagonists will develop this vasculitis.
MPGN is sometimes called mesangiocapillary glomerulonephritis or lobar glomerulonephritis. It is an immune-mediated glomerulonephritis characterized by thickening of the GBM with mesangioproliferative changes; 70% of patients have hypocomplementemia. MPGN is rare in African Americans, and idiopathic disease usually presents in childhood or young adulthood. MPGN is subdivided pathologically into Type I, Type II, and Type III disease. Type I MPGN is commonly associated with persistent hepatitis C infections, autoimmune diseases like lupus or cryoglobulinemia, or neoplastic diseases (Table 277-4). Types II and III MPGN are usually idiopathic, except in the presence of C3 nephritic factor and/or in partial lipodystrophy producing Type II disease or complement receptor deficiency in Type III disease.
Type I MPGN, the most proliferative of the three types, shows mesangial proliferation with lobular segmentation on renal biopsy and mesangial interposition between the capillary basement membrane and endothelial cells, producing a double contour sometimes called tram-tracking. Subendothelial deposits with low serum levels of C3 are typical, although 50% of patients have normal levels of C3 and occasional intra-mesangial deposits. Low serum C3 and a dense thickening of the GBM containing ribbons of dense deposits and C3 characterize Type II MPGN, sometimes called dense deposit disease. Classically, the glomerular tuft has a lobular appearance; intramesangial deposits are rarely present and subendothelial deposits are generally absent. Proliferation in Type III MPGN is less common than the other two types and is often focal; mesangial interposition is rare, and subepithelial deposits can occur along widened segments of the GBM that appear laminated and disrupted.
Type I MPGN is secondary to glomerular deposition of circulating immune complexes or their in situ formation. Types II and III MPGN may be related to "nephritic factors," which are autoantibodies that stabilize C3 convertase and allow it to activate serum C3. Patients with MPGN present with proteinuria, hematuria, and pyuria (30%), systemic symptoms of fatigue and malaise that are most common in children with Type I disease, or an acute nephritic picture with RPGN and a speedy deterioration in renal function in up to 25% of patients. Low serum C3 levels are common. Fifty percent of patients with MPGN develop end-stage disease 10 years after diagnosis, and 90% have renal insufficiency after 20 years. Nephrotic syndrome, hypertension, and renal insufficiency all predict poor outcome. In the presence of proteinuria, treatment with inhibitors of the renin-angiotensin system is prudent. Evidence for treatment with dipyridamole, coumadin, or cyclophosphamide is not strongly established nor recommended. There is some evidence supporting the efficacy of treatment of primary MPGN with steroids, particularly in children. In secondary MPGN, treating the associated infection, autoimmune disease, or neoplasms is of demonstrated benefit. Although all primary renal diseases can recur over time in transplanted renal allografts, patients with MPGN are well known to be at risk for this adverse event.
Mesangioproliferative glomerulonephritis is characterized by expansion of the mesangium, sometimes associated with mesangial hypercellularity; thin, single contoured capillary walls; and mesangial immune deposits. Clinically, it can present with varying degrees of proteinuria and, commonly, hematuria. Mesangioproliferative disease may be seen in IgA nephropathy, P. falciparum malaria, resolving postinfectious glomerulonephritis, and Class II nephritis from lupus, all of which can have a similar histologic appearance. With these secondary entities excluded, the diagnosis of primary mesangioproliferative glomerulonephritis is made in less than 15% of renal biopsies. As an immune-mediated renal lesion with deposits of IgM, C1q, and C3, the clinical course is variable. Patients with isolated hematuria may have a very benign course, and those with heavy proteinuria occasionally progress to renal failure. There is little agreement on treatment, but some clinical reports suggest benefit from use of inhibitors of the renin-angiotensin system, steroid therapy, and even cytotoxic agents.
Nephrotic syndrome classically presents with heavy proteinuria, minimal hematuria, hypoalbuminemia, hypercholesterolemia, edema, and hypertension. If left undiagnosed or untreated, some of these syndromes will progressively damage enough glomeruli to cause a fall in GFR, producing renal failure.
Therapies for various causes of nephrotic syndrome are noted under individual disease headings below. In general, all patients with hypercholesterolemia secondary to nephrotic syndrome should be treated with lipid-lowering agents since they are at increased risk for cardiovascular disease. Edema secondary to salt and water retention can be controlled with the judicious use of diuretics, avoiding intravascular volume depletion. Venous complications secondary to the hypercoagulable state associated with nephrotic syndrome can be treated with anticoagulants. The losses of various serum binding proteins, such as thyroid-binding globulin, lead to alterations in functional tests. Lastly, proteinuria itself is hypothesized to be nephrotoxic, and treatment of proteinuria with inhibitors of the renin-angiotensin system can lower urinary protein excretion.
Minimal Change Disease
MCD, sometimes known as nil lesion, causes 70–90% of nephrotic syndrome in childhood but only 10–15% of nephrotic syndrome in adults. MCD usually presents as a primary renal disease but can be associated with several other conditions, including Hodgkin's disease, allergies, or use of nonsteroidal anti-inflammatory agents; significant interstitial nephritis often accompanies cases associated with nonsteroidal use. MCD on renal biopsy shows no obvious glomerular lesion by light microscopy and is negative for deposits by immunofluorescent microscopy, or occasionally shows small amounts of IgM in the mesangium. Electron microscopy, however, consistently demonstrates an effacement of the foot process supporting the epithelial podocytes with weakening of slit-pore membranes. The pathophysiology of this lesion is uncertain. Most agree there is a circulating cytokine, perhaps related to a T cell response that alters capillary charge and podocyte integrity. The evidence for cytokine-related immune injury is circumstantial and is suggested by the presence of preceding allergies, altered cell-mediated immunity during viral infections, and the high frequency of remissions with steroids.
MCD presents clinically with the abrupt onset of edema and nephrotic syndrome accompanied by acellular urinary sediment. Less common clinical features include hypertension (30% in children, 50% in adults), microscopic hematuria (20% in children, 33% in adults), atopy or allergic symptoms (40% in children, 30% in adults), and decreased renal function (less than 5% in children, 30% in adults). The appearance of acute renal failure in adults is usually caused by intrarenal edema (nephrosarca) that is responsive to intravenous albumin and diuretics. This presentation must be distinguished from acute renal failure secondary to hypovolemia. In children, the abnormal urine principally contains albumin with minimal amounts of higher molecular weight proteins, and is sometimes called selective proteinuria. Although up to 30% of children have a spontaneous remission, all children today are treated with steroids; only children who are nonresponders are biopsied in this setting. Primary responders are patients who have a complete remission (less than 0.2 mg/24 h of proteinuria) after a single course of prednisone; steroid-dependent patients relapse as their steroid dose is tapered. Frequent relapsers have two or more relapses in the 6 months following taper, and steroid-resistant patients fail to respond to steroid therapy. Ninety to 95% of children will develop a complete remission after 8 weeks of steroid therapy, and 80–85% of adults will achieve complete remission, but only after a longer course of 20–24 weeks. Patients with steroid resistance can develop FSGS on repeat biopsy. Some hypothesize that if the first renal biopsy does not have a sample of deeper glomeruli, then the correct early diagnosis of FSGS may be missed.
Relapses occur in 70–75% of children after the first remission, and early relapse predicts multiple subsequent relapses. The frequency of relapses decreases after puberty, although there is an increased risk of relapse following the rapid tapering of steroids in all groups. Relapses are less common in adults but are more resistant to subsequent therapy. Prednisone is first-line therapy, and other immunosuppressive drugs, such as cyclophosphamide, chlorambucil, and mycophenolate mofetil, are saved for frequent relapsers, steroid-dependent, or steroid-resistant patients. Cyclosporine can induce remission, but relapse is also common when cyclosporine is withdrawn. The long-term prognosis in adults is less favorable when acute renal failure or steroid resistance occurs.
Focal Segmental Glomerulosclerosis
FSGS refers to a pattern of renal injury characterized by segmental glomerular scars that involve some but not all glomeruli; the clinical findings of FSGS largely manifest as proteinuria. When the secondary causes of FSGS are eliminated (Table 277-5), the remaining patients are considered to have FSGS. The incidence of this disease is increasing, and it now represents up to one-third of cases of nephrotic syndrome in adults and one-half of cases of nephrotic syndrome in African Americans, in whom it is seen more commonly. The pathogenesis of FSGS is probably multifactorial. Possible mechanisms include a T cell–mediated circulating permeability factor, TGF-–mediated cellular proliferation and matrix synthesis, and podocyte abnormalities associated with genetic mutations.
The pathologic changes of FSGS are most prominent in glomeruli located at the corticomedullary junction, so if the renal biopsy specimen is from superficial tissue, the lesions can be missed, which sometimes leads to a misdiagnosis of MCD. In addition to focal and segmental scarring, other variants have been described, including cellular lesions with endocapillary hypercellularity and heavy proteinuria; collapsing glomerulopathy with segmental or global glomerular collapse and a rapid decline in renal function; or the glomerular tip lesion, which seems to have a better prognosis.
FSGS can present with any level of proteinuria, hematuria, hypertension, or renal insufficiency. Nephrotic range proteinuria, African-American race, and renal insufficiency are associated with a poor outcome, with 50% of patients reaching renal failure in 6–8 years. FSGS rarely remits spontaneously, but treatment-induced remission of proteinuria significantly improves prognosis. Treatment of patients with primary FSGS should include inhibitors of the renin-angiotensin system. Based on retrospective studies, patients with nephrotic range proteinuria can be treated with steroids but respond far less often than patients with MCD. Proteinuria remits in only 20–45% of patients receiving a course of steroids over 6–9 months. Limited evidence suggests that the use of cyclosporine in steroid-responsive patients helps ensure remissions, while other cytotoxic agents confer little added benefit over steroid therapy. Primary FSGS recurs in 25–40% of patients given allografts at end-stage disease, leading to graft loss in half of those cases. The treatment of secondary FSGS typically involves treating the underlying cause and controlling proteinuria. There is no role for steroids or other immunosuppressive agents in secondary FSGS.
MGN, or membranous nephropathy as it is sometimes called, accounts for approximately 30% of cases of nephrotic syndrome in adults, with a peak incidence between the ages of 30–50 years and a male to female ratio of 2:1. It is rare in childhood and by far the most common cause of nephrotic syndrome in the elderly. In 25–30% of cases, MGN is secondary to malignancy (solid tumors of the breast, lung, colon), infection (hepatitis B, malaria, schistosomiasis), or rheumatologic disorders like lupus or rarely rheumatoid arthritis (Table 277-6).
Uniform thickening of the basement membrane along the peripheral capillary loops is seen by light microscopy on renal biopsy ; this thickening needs to be distinguished from that seen in diabetes and amyloidosis. Immunofluorescence demonstrates diffuse granular deposits of IgG and C3, and electron microscopy typically reveals electron-dense subepithelial deposits. While different stages (I–V) of progressive membranous lesions have been described, some published analyses indicate the degree of tubular atrophy or interstitial fibrosis is more predictive of progression than is the stage of glomerular disease. The presence of subendothelial deposits or the presence of tubuloreticular inclusions strongly points to a diagnosis of membranous lupus nephritis, which may precede the extrarenal manifestations of lupus. Work in Heyman nephritis, an animal model of MGN, suggests that glomerular lesions result from in situ formation of immune complexes with megalin receptor–associated protein as the putative antigen. This antigen is not found in human podocytes, but human antibodies have been described against neutral endopeptidase expressed by podocytes, hepatitis antigens B/C, Helicobacterpylori antigens, tumor antigens, and thyroglobulin.
Eighty percent of patients with MGN present with nephrotic syndrome and nonselective proteinuria. Microscopic hematuria is seen in up to 50% of patients. Spontaneous remissions occur in 20–33% of patients and often occur late in the course after years of nephrotic syndrome. One-third of patients continue to have relapsing nephrotic syndrome but maintain normal renal function, and approximately another third of patients develop renal failure or die from the complications of nephrotic syndrome. Male gender, older age, hypertension, and the persistence of proteinuria are associated with worse prognosis. Although thrombotic complications are a feature of all nephrotic syndromes, MGN has the highest reported incidences of renal vein thrombosis, pulmonary embolism, and deep vein thrombosis. Prophylactic anticoagulation is controversial but has been recommended for patients with severe or prolonged proteinuria in the absence of risk factors for bleeding.
In addition to the treatment of edema, dyslipidemia, and hypertension, inhibition of the renin-angiotensin system is recommended. Therapy with immunosuppressive drugs is also recommended for patients with primary MGN and persistent proteinuria (>3.0 g/24 h). The choice of immunosuppressive drugs for therapy is controversial, but current recommendations based on small clinical studies are to treat with steroids and cyclophosphamide, chlorambucil, or cyclosporine. Experience with mycophenolate mofetil or anti-CD20 antibody is even more limited.
Diabetic nephropathy is the single most common cause of chronic renal failure in the United States, accounting for 45% of patients receiving renal replacement therapy, and is a rapidly growing problem worldwide. The dramatic increase in the number of patients with diabetic nephropathy reflects the epidemic increase in obesity, metabolic syndrome, and Type 2 diabetes mellitus. Approximately 40% of patients with Types 1 or 2 diabetes develop nephropathy, but due to the higher prevalence of Type 2 diabetes (90%) compared to Type 1 (10%), the majority of patients with diabetic nephropathy have Type 2 disease. Renal lesions are more common in African-American, Native American, Polynesian, and Maori populations. Risk factors for the development of diabetic nephropathy include hyperglycemia, hypertension, dyslipidemia, smoking, a family history of diabetic nephropathy, and gene polymorphisms affecting the activity of the renin-angiotensin-aldosterone axis.
Within 1–2 years after the onset of clinical diabetes, morphologic changes appear in the kidney. Thickening of the GBM is a sensitive indicator for the presence of diabetes but correlates poorly with the presence or absence of clinically significant nephropathy. The composition of the GBM is altered notably with a loss of heparan sulfate moieties that form the negatively charged filtration barrier. This change results in increased filtration of serum proteins into the urine, predominately negatively charged albumin. The expansion of the mesangium due to the accumulation of extracellular matrix correlates with the clinical manifestations of diabetic nephropathy. This expansion in mesangial matrix can be associated with the development of mesangial sclerosis. Some patients also develop eosinophilic, PAS+ nodules called nodular glomerulosclerosis or Kimmelstiel-Wilson nodules. Immunofluorescence microscopy often reveals the nonspecific deposition of IgG (at times in a linear pattern) or complement staining without immune deposits on electron microscopy. Prominent vascular changes are frequently seen with hyaline and hypertensive arteriosclerosis. This is associated with varying degrees of chronic glomerulosclerosis and tubulointerstitial changes. Renal biopsies from patients with Types 1 and 2 diabetes are largely indistinguishable.
These pathologic changes are the result of a number of postulated factors. Multiple lines of evidence support an important role for increases in glomerular capillary pressure (intraglomerular hypertension) in alterations in renal structure and function. Direct effects of hyperglycemia on the actin cytoskeleton of renal mesangial and vascular smooth-muscle cells as well as diabetes-associated changes in circulating factors such as atrial naturetic factor, angiotensin II, and insulin-like growth factor (IGF) may account for this. Sustained glomerular hypertension increases matrix production, alterations in the GBM with disruption in the filtration barrier (and hence proteinuria) and glomerulosclerosis. A number of factors have also been identified which alter matrix production, including the accumulation of advanced glycosylation end products, circulating factors including growth hormone, IGF-I, angiotensin II, connective tissues growth factor, TGF-, and dyslipidemia.
The natural history of diabetic nephropathy in patients with Types 1 and 2 diabetes is similar. However, since the onset of Type 1 diabetes is readily identifiable and the onset of Type 2 diabetes is not, a patient newly diagnosed with Type 2 diabetes may have renal disease for many years before nephropathy is discovered and presents as advanceddiabetic nephropathy. At the onset of diabetes, renal hypertrophy and glomerular hyperfiltration are present. The degree of glomerular hyperfiltration correlates with the subsequent risk of clinically significant nephropathy. In the approximately 40% of patients with diabetes who develop diabetic nephropathy, the earliest manifestation is an increase in albuminuria detected by sensitive radioimmunoassay (Table 277-1). Albuminuria in the range of 30–300 mg/24 h is called microalbuminuria. In patients with Types 1 or 2 diabetes, microalbuminuria appears 5–10 years after the onset of diabetes. It is currently recommended to test patients with Type 1 disease for microalbuminuria 5 years after diagnosis of diabetes and yearly thereafter, and, because the time of onset of Type 2 diabetes is often unknown, to test Type 2 patients at the time of diagnosis of diabetes and yearly thereafter.
Patients with small rises in albuminuria increase their levels of urinary albumin excretion, typically reaching dipstick positive levels of proteinuria (>300 mg albuminuria) 5–10 years after the onset of early albuminuria. Microalbuminuria is a potent risk factor for cardiovascular events and death in patients with Type 2 diabetes. Many patients with Type 2 diabetes and microalbuminuria succumb to cardiovascular events before they progress to proteinuria or renal failure. Proteinuria in frank diabetic nephropathy can be variable, ranging from 500 mg to 25 g/24 h, and is often associated with nephrotic syndrome. More than 90% of patients with Type 1 diabetes and nephropathy have diabetic retinopathy, so the absence of retinopathy in Type 1 patients with proteinuria should prompt consideration of a diagnosis other than diabetic nephropathy; only 60% of patients with Type 2 diabetes with nephropathy have diabetic retinopathy. There is a highly significant correlation between the presence of retinopathy and the presence of Kimmelstiel-Wilson nodules . Also, characteristically, patients with advanced diabetic nephropathy have normal to enlarged kidneys, in contrast to other glomerular diseases where kidney size is usually decreased. Using the above epidemiologic and clinical data, and in the absence of other clinical or serologic data suggesting another disease, diabetic nephropathy is usually diagnosed without a renal biopsy. After the onset of proteinuria more than 500 mg/24 h, renal function inexorably declines, with 50% of patients reaching renal failure in 5–10 years; thus, from the earliest stages of microalbuminuria, it usually takes 10–20 years to reach end-stage renal disease. Hypertension may predict which patients develop diabetic nephropathy, as the presence of hypertension accelerates the rate of decline in renal function. Once renal failure appears, however, survival on dialysis is far shorter for patients with diabetes compared to other dialysis patients; some diabetics do better clinically if they are started on dialysis before they reach advanced renal failure. Survival is best for patients with Type 1 diabetes who receive a transplant from a living related donor.
Good evidence supports the benefits of blood sugar and blood pressure control as well as inhibition of the renin-angiotensin system in retarding the progression of diabetic nephropathy. In patients with Type 1 diabetes, intensive control of blood sugar clearly prevents the development or progression of diabetic nephropathy. The evidence in patients with Type 2 disease, although less compelling, also supports intensive control of blood sugar. Controlling systemic blood pressure to levels of 130/80 mmHg or less decreases renal and cardiovascular adverse events in this high-risk population. The vast majority of patients with diabetic nephropathy require three or more antihypertensive drugs to achieve this goal. Drugs that inhibit the renin-angiotensin system, independent of their effects on systemic blood pressure, have been repeatedly shown to slow the progression of diabetic nephropathy at early (microalbuminuria) and late (proteinuria with reduced glomerular filtration) stages, independent of any effect they may have on systemic blood pressure.
Since angiotensin II increases efferent arteriolar resistance and, hence, glomerular capillary pressure, one key mechanism for the efficacy of ACE inhibitors or angiotensin receptor blockers (ARBs) is reducing glomerular hypertension. Patients with Type 1 diabetes for 5 years who develop albuminuria or declining renal function should be treated with ACE inhibitors. Patients with Type 2 diabetes and microalbuminuria or proteinuria may be treated with ACE inhibitors or ARBs.
Glomerular Deposition Diseases
Plasma cell dyscrasias producing excess light chain immunoglobulin sometimes lead to the formation of glomerular and tubular deposits that cause heavy proteinuria and renal failure; the same is true for the accumulation of serum amyloid A protein fragments seen in several inflammatory diseases. This broad group of proteinuric patients has glomerular deposition disease.
Light Chain Deposition Disease
The biochemical characteristics of nephrotoxic light chains produced in light chain malignancies typically confers a specific pattern of renal injury in each individual patient; that of either cast nephropathy, which causes renal failure but not heavy proteinuria, amyloidosis, or light chain deposition disease, which produce nephrotic syndrome with renal failure. These latter patients produce kappa light chains that do not have the biochemical features necessary to form amyloid fibrils. Instead, they self-aggregate and form granular deposits along the glomerular capillary and mesangium, tubular basement membrane, and Bowman's capsule. When predominant in glomeruli, nephrotic syndrome develops, and about 70% of patients progress to dialysis. Light-chain deposits are not fibrillar and do not stain with Congo red, but they are easily detected with anti-light–chain antibody using immunofluorescence, or as granular deposits on electron microscopy. A combination of the light-chain rearrangement, self-aggregating properties at neutral pH, and abnormal metabolism probably contribute to the deposition. Treatment for light-chain deposition disease is treatment of the primary disease. As so many patients with light-chain deposition disease progress to renal failure, the overall prognosis is grim.
Most renal amyloidosis is either the result of primary fibrillar deposits of immunoglobulin light chains [amyloid L (AL)], or secondary to fibrillar deposits of serum amyloid A (AA) protein fragments. Even though both occur for different reasons, their clinicopathophysiology is quite similar and will be discussed together. Amyloid infiltrates the liver, heart, peripheral nerves, carpal tunnel, upper pharynx, and kidney, producing restrictive cardiomyopathy, hepatomegaly, macroglossia, and heavy proteinuria sometimes associated with renal vein thrombosis. In systemic AL amyloidosis, also called primary amyloidosis, light chains produced in excess by clonal plasma cell dyscrasias are made into fragments by macrophages so they can self-aggregate at acid pH. A disproportionate number of these light chains (75%) are of the lambda class. About 10% of these patients have overt myeloma with lytic bone lesions and infiltration of the bone marrow with more than 30% plasma cells; nephrotic syndrome is common, and about 20% of patients progress to dialysis. AA amyloidosis is sometimes called secondary amyloidosis and also affects the kidney with nephrotic syndrome. It is due to deposition of -pleated sheets of serum amyloid A protein, an acute phase reactant whose physiologic function is unknown.
Forty percent of patients with AA amyloid have rheumatoid arthritis, and another 10% have ankylosing spondylitis or psoriatic arthritis; the rest derive from other lesser causes. Less common in Western countries but more common in Mediterranean regions, particularly in Sephardic and Iraqi Jews, is familial Mediterranean fever (FMF). FMF is caused by a mutation in the gene encoding pyrin, while Muckle-Wells syndrome, a related disorder, results from a mutation in cryropyrin; both proteins are important in the apoptosis of leukocytes early in inflammation. Receptor mutations in TNFR1–associated periodic syndrome also produce chronic inflammation and secondary amyloidosis. Fragments of serum amyloid A protein increase and self-aggregate by attaching to receptors for advanced glycation end products in the extracellular environment; nephrotic syndrome is common, and about 40–60% of patients progress to dialysis. AA and AL amyloid fibrils are detectable with Congo red or in more detail with electron microscopy (Fig. e9-13). Biopsy of involved liver or kidney is diagnostic 90% of the time when the pretest probability is high; abdominal fat pad aspirates are positive about 70% of the time, but apparently less so when looking for AA amyloid. Amyloid deposits are distributed along blood vessels and in the mesangial regions of the kidney. The treatment for primary amyloidosis is not particularly effective; melphalan and autologous hematopoietic stem cell transplantation can delay the course of disease in about 30% of patients. Secondary amyloidosis is also relentless unless the primary disease can be controlled. Some new drugs in development that disrupt the formation of fibrils may be available in the future.
There is no agreement on whether fibrillary glomerulonephritis and immunotactoid glomerulonephritis are different or one and the same. Both are hard to distinguish by clinical presentation but have some apparent differences with electron microscopy. Fibrillar/microtubular deposits of oligoclonal or oligotypic immunoglobulins and complement appear in the mesangium and along the glomerular capillary wall. In fibrillary glomerulonephritis the fibrils are smaller and more randomly distributed than in immunotactoid glomerulonephritis. Congo red stains are negative in both disorders. The cause of this "nonamyloid" glomerulopathy is mostly idiopathic; reports of immunotactoid glomerulonephritis describe an occasional association with chronic lymphocytic leukemia or B cell lymphoma. Both disorders appear in adults in the fourth decade with moderate to heavy proteinuria, hematuria, and a wide variety of histologic lesions, including DPGN, MPGN, MGN, or mesangioproliferative glomerulonephritis. Nearly half of patients will develop renal failure over a few years. There is no consensus on treatment of this uncommon disorder.
Fabry's disease is an X-linked inborn error of globotriaosylceramide metabolism secondary to deficient lysosomal -galactosidase A activity, resulting in excessive intracellular storage of globotriaosylceramide. Affected organs include the vascular endothelium, heart, brain, and kidneys. Classically, Fabry's disease presents in childhood in males with multi-organ involvement. Hemizygotes with hypomorphic mutations sometimes present in the fourth to sixth decade with single organ involvement. Rarely, dominant-negative -galactosidase A mutations or female heterozygotes with unfavorable X inactivation present with mild single-organ involvement. Renal biopsy reveals enlarged glomerular visceral epithelial cells packed with small clear vacuoles containing globotriaosylceramide; vacuoles may also be found in parietal and tubular epithelia. These vacuoles of electron-dense materials in parallel arrays (zebra bodies) are easily seen on electron microscopy. Ultimately, glomeruli develop FSGS. The nephropathy of Fabry's disease typically presents in the third decade as mild to moderate proteinuria, sometimes with microscopic hematuria or nephrotic syndrome. Urinalysis may reveal oval fat bodies and birefringent glycolipid globules under polarized light (Maltese cross). Renal biopsy is necessary for definitive diagnosis. Progression to renal failure occurs by the fourth or fifth decade. Treatment with recombinant -galactosidase A has been demonstrated to clear microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin.
Several diseases can present with catastrophic hemoptysis and glomerulonephritis associated with varying degrees of renal failure. The usual causes include Goodpasture's syndrome, Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss vasculitis, and, rarely, Henoch-Schönlein purpura or cryoglobulinemia. Each of these diseases can also present without hemoptysis and are discussed in detail in "Acute Nephritic Syndromes," above. Pulmonary bleeding in this setting is life-threatening and often results in airway intubation, and acute renal failure requires dialysis in the intensive care unit. Diagnosis is difficult initially because biopsies and serologic testing take time
Treatment with plasmapheresis and methylprednisolone is often empiric and temporizing until results of testing are available.
Basement Membrane Syndromes
All kidney epithelia, including podocytes, rest on basement membranes assembled into a planar surface through the interweaving of collagen IV with laminins, nidogen, and sulfated proteoglycans. Structural abnormalities in GBMs associated with hematuria are characteristic of several familial disorders related to the expression of collagen IV genes. The extended family of collagen IV contains six chains, which are expressed in different tissues at different stages of embryonic development. All epithelial basement membranes early in human development are composed of interconnected triple-helical protomers rich in 1.1.2(IV) collagen. Some specialized tissues undergo a developmental switch replacing 1.1.2(IV) protomers with an 3.4.5(IV) collagen network; this switch occurs in the kidney (glomerular and tubular basement membrane), lung, testis, cochlea, and eye, while an 5.5.6(IV) network appears in skin, smooth muscle, and esophagus and along Bowman's capsule in the kidney. This switch probably occurs because the 3.4.5(IV) network is more resistant to proteases and ensures the structural longevity of critical tissues. When basement membranes are the target of glomerular disease, they produce moderate proteinuria, some hematuria, and progressive renal failure.
Autoimmune disease where antibodies are directed against the 3 NC1 domain of collagen IV produces an anti-GBM disease often associated with RPGN and/or a pulmonary-renal syndrome called Goodpasture's syndrome. Discussion of this disease is covered in "Acute Nephritic Syndromes," above.
Classically, patients with Alport's syndrome develop hematuria, thinning and splitting of the GBMs, mild proteinuria (less than 1–2 g/24 h), and chronic glomerulosclerosis, leading to renal failure in association with sensorineural deafness. Some patients develop lenticonus of the anterior lens capsule and, rarely, mental retardation or leiomyomatosis. Approximately 85% of patients with Alport's syndrome have an X-linked inheritance of mutations in the 5(IV) collagen chain on chromosome Xq22–24. Female carriers have variable penetrance depending on the type of mutation or the degree of mosaicism created by X inactivation. Fifteen percent of patients have autosomal recessive disease of the 3(IV) or 4(IV) chains on chromosome 2q35–37. Rarely, some kindred have an autosomal dominant inheritance of dominant-negative mutations in 3(IV) or 4(IV) chains.
Pedigrees with this syndrome are quite variable in their rate and frequency of tissue damage leading to organ failure. Patients with nonsense or missense mutations, reading frame shifts, or large deletions generally develop renal failure and sensorineural deafness by age 30 (juvenile form), while patients with splice variants, exon skipping, or missense mutations of -helical glycines generally deteriorate after the age of 30 (adult form) with mild or late deafness. Early severe deafness or lenticonus suggest a poorer prognosis.
Alport's patients early in their disease typically have thin basement membranes on renal biopsy, which thicken over time into multilamellations surrounding lucent areas that often contain granules of varying density—the so-called split basement membrane. In any Alport kidney there are areas of thinning mixed with splitting of the GBM. Tubules drop out, glomeruli scar, and the kidney eventually succumbs to interstitial fibrosis. Primary treatment is control of systemic hypertension and use of ACE inhibitors to slow renal progression. Although patients who receive renal allografts usually develop anti-GBM antibodies directed toward the collagen epitopes absent in their native kidney, overt Goodpasture's syndrome is uncommon and graft survival is good.
Thin Basement Membrane Disease
Some variants of Alport's syndrome are now recognized as a subpopulation of patients with thin basement membrane disease. Thin basement membranes are found in 5–10% of the so-called normal population. These subclinical patients have normal blood pressure and little proteinuria, and they rarely progress to renal failure. If they present with hematuria, they are often given the diagnosis of benign familial hematuria. Many of these patients have mutations in the same 3(IV) or 4(IV) collagen genes associated with autosomal recessive or dominant Alport's syndrome. Clearly, the boundary between nonprogressive Alport's syndrome and benign familial hematuria is quite variable, as there is a spectrum of clinical penetrance.
Patients with nail-patella syndrome develop iliac horns on the pelvis and dysplasia of the dorsal limbs involving the patella, elbows, and nails, variably associated with neural-sensory hearing impairment, glaucoma, and abnormalities of the GBM and podocytes, leading to hematuria, proteinuria, and FSGS. The syndrome is autosomal-dominant, with haploinsufficiency for the LIM homeodomain transcription factor LMX1B; pedigrees are extremely variable in the penetrance for all features of the disease. LMX1B regulates the expression of genes encoding 3 and 4 chains of collagen IV, interstitial type III collagen, podocin, and CD2AP that help form the slit-pore membranes connecting podocytes. Mutations in the LIM domain region of LMX1B are associated with glomerulopathy, and renal failure appears in as many as 30% of patients. Proteinuria or isolated hematuria is discovered throughout life, but usually by the third decade, and is inexplicably more common in females. On renal biopsy there is lucent damage to the lamina densa of the GBM, an increase in collagen III fibrils along glomerular capillaries and in the mesangium, and damage to the slit-pore membrane, producing heavy proteinuria not unlike that seen in congenital nephrotic syndrome. Patients with renal failure do well with transplantation.
A variety of diseases result in classic vascular injury to the glomerular capillaries. Most of these processes also damage blood vessels elsewhere in the body. The group of diseases discussed here lead to vasculitis, renal endothelial injury, thrombosis, ischemia, and/or lipid-based occlusions.
Aging in the developed world is commonly associated with the occlusion of coronary and systemic blood vessels. The reasons for this include obesity, insulin resistance, smoking, hypertension, and diets rich in lipids that deposit in the arterial and arteriolar circulation, producing local inflammation and fibrosis of small blood vessels. When the renal arterial circulation is involved, the glomerular microcirculation is damaged, leading to chronic nephrosclerosis. Patients with GFRs less than 60 mL/min have more cardiovascular events and hospitalizations than those with higher filtration rates. Several aggressive lipid disorders can accelerate this process, but most of the time atherosclerotic progression to chronic nephrosclerosis is associated with poorly controlled hypertension. Approximately 10% of glomeruli are normally sclerotic by age 40, rising to 20% by age 60 and 30% by age 80. Serum lipid profiles in humans are greatly affected by apolipoprotein E polymorphisms; the E4 allele is accompanied by increases in serum cholesterol and is more closely associated with atherogenic profiles in patients with renal failure. Mutations in E2 alleles, particularly in Japanese patients, produce a specific renal abnormality called lipoprotein glomerulopathy associated with glomerular lipoprotein thrombi and capillary dilation.
Uncontrolled systemic hypertension causes permanent damage to the kidneys in about 6% of patients with elevated blood pressure. As many as 27% of patients with end-stage kidney disease have hypertension as a primary cause. Although there is not a clear correlation between the extent or duration of hypertension and the risk of end-organ damage, hypertensive nephrosclerosis is fivefold more frequent in African Americans than Caucasians. Associated risk factors for progression to end-stage kidney disease include age, sex, race, smoking, hypercholesterolemia, duration of hypertension, low birth weight, and preexisting renal injury. Kidney biopsies in patients with hypertension, microhematuria, and moderate proteinuria demonstrate arteriolosclerosis, chronic nephrosclerosis, and interstitial fibrosis in the absence of immune deposits. Today, based on a careful history, physical examination, urinalysis, and some serologic testing, the diagnosis of chronic nephrosclerosis is usually inferred without a biopsy. Treating hypertension is the best way to avoid progressive renal failure; most guidelines recommend lowering blood pressure to less than 130/80 mmHg if there is preexisting diabetes or kidney disease. In the presence of kidney disease, most patients begin therapy with two drugs, classically a thiazide diuretic and an ACE inhibitor; many will require three drugs. There is strong evidence in African Americans with hypertensive nephrosclerosis that therapy initiated with an ACE inhibitor can slow the rate of decline in renal function independent of systemic blood pressure. Patients with lower levels of hypertension are usually started on a thiazide diuretic or an ACE inhibitor alone. Malignant acceleration of hypertension can complicate the course of chronic nephrosclerosis, particularly in the setting of scleroderma or cocaine use. The hemodynamic stress of malignant hypertension causes fibrinoid necrosis of small blood vessels, thrombotic microangiography, a nephritic urinalysis, and acute renal failure. In the setting of renal failure, chest pain, or papilledema, the condition is treated as a hypertensive emergency. Slightly lowering the blood pressure often produces an immediate reduction in GFR that improves as the vascular injury attenuates and autoregulation of blood vessel tone is restored.
Aging patients with clinical complications from atherosclerosis sometimes shower cholesterol crystals into the circulation—either spontaneously or, more commonly, following an endovascular procedure with manipulation of the aorta—or with use of systemic anticoagulation. Spontaneous emboli may shower acutely or shower subacutely and somewhat more silently. Irregular emboli trapped in the microcirculation produce ischemic damage that induces an inflammatory reaction. Depending on the location of the atherosclerotic plaques releasing these cholesterol fragments, one may see cerebral transient ischemic attacks; livedo reticularis in the lower extremities; Hollenhorst plaques in the retina with visual field cuts; necrosis of the toes; and acute glomerular capillary injury leading to focal glomerulosclerosis sometimes associated with hematuria, mild proteinuria, and loss of renal function, which typically progresses over a few years. Occasional patients have fever, eosinophilia, or eosinophiluria. A skin biopsy of an involved area may be diagnostic. Since tissue fixation dissolves the cholesterol, one typically sees only residual, biconvex clefts in the vessel. There is no therapy to reverse embolic occlusions, and steroids do not help. Controlling blood pressure and lipids and cessation of smoking are usually recommended for prevention.
Sickle Cell Disease
Although individuals with SA-hemoglobin are usually asymptomatic, most will gradually develop hyposthenuria due to subclinical infarction of the renal medulla, thus predisposing them to volume depletion. Patients with homozygous SS-sickle cell disease develop chronic vasoocclusive disease in many organs. Polymers of deoxygenated SS-hemoglobin distort the shape of red blood cells. These cells attach to endothelia and obstruct small blood vessels, producing frequent, random, and painful sickle cell crises over time. Vessel occlusions in the kidney produce glomerular hypertension, FSGS, interstitial nephritis, and renal infarction associated with hyposthenuria, microscopic hematuria, and even gross hematuria; some patients also present with MPGN. By the second or third decade of life, persistent vasoocclusive disease in the kidney leads to varying degrees of renal failure, and some patients end up on dialysis. Treatment is directed to reducing the frequency of painful crises and administering ACE inhibitors in the hope of delaying a progressive decline in renal function. Sickle cell patients can have transplantations, and renal graft survival is comparable to African Americans given transplantations for other reasons.
Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) represent a spectrum of thrombotic microangiopathies. TTP and HUS share the general features of idiopathic thrombocytopenic purpura, hemolytic anemia, fever, renal failure, and neurologic disturbances. When patients have more evidence of renal injury, their condition tends to be called HUS, and when there is more neurologic disease, it is considered to be TTP. In adults there is often a mixture of both, which is why they are often called TTP/HUS. On examination of kidney tissue there is evidence of glomerular capillary endotheliosis associated with platelet thrombi, damage to the capillary wall, and formation of fibrin material in and around glomeruli (Fig. e9-21). These tissue findings are similar to what is seen in preeclampsia/HELLP (hemolysis, elevated liver enzymes, and low platelet count syndrome), malignant hypertension, and the antiphospholipid syndrome. TTP/HUS is also seen in pregnancy; with the use of oral contraceptives or quinine; in renal transplant patients given OKT3 for rejection; in patients taking the calcineurin inhibitors cyclosporine and tacrolimus or in patients taking the antiplatelet agents ticlopidine and clopidogrel; or following HIV infection.
Although there is no agreement on how much they share a final common pathophysiology, two general groups of patients are recognized: childhood HUS associated with enterohemorrhagic diarrhea and TTP-HUS in adults. Childhood HUS is caused by a toxin released by Escherichia coli O157:H7 and occasionally by Shigella dysenteriae. This shiga toxin (veratoxin) directly injures endothelia, enterocytes, and renal cells, causing apoptosis, platelet clumping, and intravascular hemolysis by binding to the glycolipid receptors (Gb3). These receptors are more abundant along endothelia in children compared to adults. In familial cases of adult TTP/HUS, there is a genetic deficiency of the ADAMTS13 metalloprotease that cleaves large multimers of von Willebrand's factor. Absent ADAMTS13, these large multimers cause platelet clumping and intravascular hemolysis. An antibody to ADAMTS13 is found in many sporadic cases of adult TTP/HUS, but not all; many patients also have antibodies to the thrombospondin receptor on selected endothelial cells in small vessels or increased levels of plasminogen-activator inhibitor 1 (PAI-1). The treatment of childhood HUS or adult TTP/HUS is daily plasmapheresis, which can be lifesaving. Plasmapheresis is given until the platelet count rises, but in relapsing patients it may need to be continued well after the platelet count improves, and in resistant patients twice-daily exchange may be helpful. Most patients respond within 2 weeks of daily plasmapheresis. Since TTP/HUS often has an autoimmune basis, there is an anecdotal role in relapsing patients for using splenectomy, steroids, immunosuppressive drugs, or anti-CD20 antibody. Patients with childhood HUS from infectious diarrhea are not given antibiotics, as antibiotics are thought to accelerate the release of the toxin and the diarrhea is usually self-limited.
Antiphospholipid syndrome develops in patients expressing antibodies to anionic phospholipids, particularly 2 glycoprotein 1. Half of the patients have no obvious cause, a few are pregnant, some are already receiving hemodialysis or have a renal allograft, and the rest have a primary glomerulonephritis (nil lesion or membranous nephropathy) or a rheumatologic disease such as SLE. Lupus patients also often coexpress a lupus anticoagulant, with elevation in the activated partial tissue thromboplastin time. Clinical presentation of the catastrophic form of antiphospholipid syndrome appears as mixed thrombosis of the arterial and venous circulation with varying degrees of thrombocytopenia, hemolytic anemia, deep vein thrombosis, transient ischemic attacks, pulmonary embolism, and spontaneous abortions; lesser degrees of disease are more common. The kidneys are injured in this syndrome in approximately 25% of patients, particularly those with IgG antibodies. Some patients develop acute renal failure, while others suffer subclinical damage over time. Patients who present with acute flank pain and renal vein thrombosis in the setting of proteinuria should always be checked for antiphospholipid antibodies. Clinically, the antiphospholipid syndrome can wax and wane, and many patients have recurrences; less than 10% present with catastrophic multi-organ involvement and acute renal failure. Dialysis patients with antiphospholipid syndrome experience frequent occlusion of their arteriovenous graft. The urinalysis in most patients typically shows a mixed picture of moderate proteinuria (1–2 g/24 h) and hematuria. Glomerular capillaries and large and small renal arteries and veins occlude, accompanied by ischemic mesangiolysis and vessel hyperplasia, leading eventually to chronic glomerulosclerosis and interstitial fibrosis. Evidence of antiphospholipid syndrome on biopsy can usually be distinguished as an added complication of an underlying renal disease, particularly lupus nephritis. The mainstay of treatment for antiphospholipid syndrome is warfarin. There is also evidence of vasculitis in many patients due to complement-fixing antiphospholipid antibodies, which responds to the addition of steroids. Acute renal failure sometimes responds to removal of antiphospholipid antibodies with plasmapheresis and adjustment of immunosuppression where clinically indicated.
Infectious Disease–Associated Syndromes
A number of infectious diseases will injure the glomerular capillaries as part of a systemic reaction producing an immune response or from direct infection of renal tissue. Evidence of this immune response is collected by glomeruli in the form of immune deposits that damage the kidney, producing moderate proteinuria and hematuria. Some of these infectious diseases represent the most common causes of glomerulonephritis worldwide.
This form of glomerulonephritis is one of the classic complications of streptococcal infection. The discussion of this disease can be found in the section on acute nephritic syndromes.
Subacute Bacterial Endocarditis
Renal injury from persistent bacteremia absent the continued presence of a foreign body, regardless of cause, is treated presumptively as if the patient has endocarditis. The discussion of this disease can be found in "Acute Nephritic Syndromes," above.
Human Immunodeficiency Virus
HIV-associated nephropathy is seen after an interval of approximately 2.5 years from discovery of HIV, and many patients have low CD4 counts. Most lesions on renal biopsy show FSGS followed by MPGN. Other less common renal lesions include DPGN, IgA nephropathy, MCD, and membranous or mesangioproliferative glomerulonephritis. The disease affects up to 10% of HIV-infected patients and is more commonly seen in African-American men than in Caucasians, and in intravenous drug users or homosexuals. The FSGS characteristically reveals collapse of the glomerular capillary tuft called collapsing glomerulopathy, visceral epithelial cell swelling, microcystic dilatation of renal tubules, and tubuloreticular inclusions. Renal epithelial cells express replicating HIV virus, but host immune responses also play a role in the pathogenesis. MPGN and DPGN have been reported more commonly in HIV-infected Caucasians and in patients co-infected with hepatitis B or C. HIV-associated TTP has also been reported.
HIV patients with FSGS typically present with nephrotic-range proteinuria and hypoalbuminemia, but unlike patients with other etiologies for nephrotic syndrome, they do not commonly have hypertension, edema, or hyperlipidemia. Renal ultrasound also reveals large, echogenic kidneys, and renal function in some patients declines rapidly. Treatment with inhibitors of the renin-angiotensin system decreases the proteinuria. Although evidence from large well-designed clinical trials is lacking, many feel that effective antiretroviral therapy benefits both the patient and the kidney. Dismal survival once renal failure is reached has improved, and many centers now offer renal allografts to select HIV patients.
Hepatitis B and C
Chronic hepatitis B infection can be associated with polyarteritis nodosa, more commonly in adults than children. Typically, however, infected patients only present with microscopic hematuria, nonnephrotic or nephrotic-range proteinuria, and hypertension. Alternatively, the hepatitis B carrier state can produce a MGN that is more common in children than adults or MPGN that is more common in adults than in children. Renal histology is indistinguishable from idiopathic MGN or Type I MPGN. There are no good treatment guidelines, but interferon and lamivudine have been used to some effect in small studies. Children have a good prognosis, with 66% achieving spontaneous remission within 3 years. In contrast, 30% of adults have renal insufficiency and 10% have renal failure 5 years after diagnosis.
Up to 30% of patients with chronic hepatitis C infection have some renal manifestations. Patients often present with cryoglobulinemia and nephrotic syndrome, microscopic hematuria, abnormal liver function tests, depressed C3 levels, anti-HCV antibodies, and viral RNA in the blood. The renal lesions most commonly seen, in order of decreasing frequency, are cryoglobulinemic glomerulonephritis, MGN, and Type I MPGN. Treatment aims at reducing the level of the infection.
Other viral infections are occasionally associated with glomerular lesions, but cause and effect are not well-established. These viral infections and their respective glomerular lesions include: cytomegalovirus producing MPGN; influenza and anti-GBM disease; measles-associated endocapillary proliferative glomerulonephritis, with measles antigen in the capillary loops and mesangium; parvovirus causing mild proliferative or mesangioproliferative glomerulonephritis; mumps and mesangioproliferative glomerulonephritis; Epstein-Barr virus producing MPGN, diffuse proliferative nephritis, or IgA nephropathy; dengue hemorrhagic fever causing endocapillary proliferative glomerulonephritis; and coxsackie virus producing focalglomerulonephritis or DPGN.
Secondary syphilis, with rash and constitutional symptoms, develops weeks to months after the chancre first appears and occasionally presents with the nephrotic syndrome from MGN caused by subepithelial immune deposits containing treponemal antigens. The diagnosis is confirmed with non-treponemal and treponemal tests for Treponema pallidum. The renal lesion responds to treatment with penicillin or an alternative drug, if allergic. Additional testing for other sexually transmitted diseases is an important part of disease management.
Despite aggressive eradication programs, approximately 400,000 new cases of leprosy appear annually worldwide. The diagnosis is best made in patients with multiple skin lesions accompanied by sensory loss in affected areas, using skin smears showing paucibacillary or multibacillary infection (WHO criteria). Leprosy is caused by infection with Mycobacterium leprae and can be classified by Ridley-Jopling criteria into various types: tuberculoid, borderline tuberculoid, mid-borderline and borderline lepromatous, and lepromatous. In some series, all cases with borderline lepromatous and lepromatous types of leprosy have various forms of glomerulonephritis. Most common is focal glomerulonephritis followed by mesangioproliferative glomerulonephritis or renal amyloidosis; much less common are the renal lesions of DPGN and MPGN. Treatment with dapsone, rifampicin, and clofazimine can irradiate the infection in nearly all patients.
There are 300–500 million incident cases of malaria each year worldwide, and the kidney is commonly involved. Glomerulonephritis is due to immune complexes containing malarial antigens that are implanted in the glomerulus. In malaria from P. falciparum, mild proteinuria is associated with subendothelial deposits, mesangial deposits, and mesangioproliferative glomerulonephritis that usually resolve with treatment. In quartian malaria from infection with P. malariae, children are more commonly affected and renal involvement is more severe. Transient proteinuria and microscopic hematuria can resolve with treatment of the infection. However, resistant nephrotic syndrome with progression to renal failure over 3–5 years does happen, as less than 50% of patients respond to steroid therapy. Affected patients with nephrotic syndrome have thickening of the glomerular capillary walls, with subendothelial deposits of IgG, IgM, and C3 associated with a sparse membranoproliferative lesion. The rare mesangioproliferative glomerulonephritis reported with P. vivax or P. ovale typically has a benign course.
Schistosomiasis affects more than 300 million people worldwide and primarily involves the urinary and gastrointestinal tracts. Glomerular involvement varies with the specific strain of schistosomiasis; Schistosoma mansoni is most commonly associated with clinical renal disease, and the glomerular lesions can be classified: Class I is a mesangioproliferative glomerulonephritis; Class II is an extracapillary proliferative glomerulonephritis; Class III is a membranoproliferative glomerulonephritis; Class IV is a focal segmental glomerulonephritis; and Class V lesions have amyloidosis. Classes I–II often remit with treatment of the infection, but Classes III and IV lesions are associated with IgA immune deposits and progress despite antiparasitic and/or immunosuppressive therapy.
Renal involvement with toxoplasmosis infections is rare. When it occurs, patients present with nephrotic syndrome and have a histologic picture of MPGN. Fifty percent of patients with leishmaniasis will have mild to moderate proteinuria and microscopic hematuria, but renal insufficiency is rare. Acute DPGN, MGN, and mesangioproliferative glomerulonephritis have all been observed on biopsy. The nematodes, filariasis and trichinosis, can be associated with glomerular injury presenting with proteinuria, hematuria, and a variety of histologic lesions that typically resolve with eradication of the infection.